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Fas/CD95 Deficiency in Apc.sup.Min/+ Mice Increases Intestinal Tumor Burden
Fas, a member of the tumor necrosis family, is responsible for initiating the apoptotic pathway when bound to its ligand, Fas-L. Defects in the Fas-mediated apoptotic pathway have been reported in colorectal cancer. In the present study, a variant of the Apc.sup.Min/+ mouse, a model for the human co...
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Published in: | PloS one 2010-02, Vol.5 (2), p.e9070 |
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Main Authors: | , , , |
Format: | Article |
Language: | English |
Subjects: | |
Online Access: | Get full text |
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Summary: | Fas, a member of the tumor necrosis family, is responsible for initiating the apoptotic pathway when bound to its ligand, Fas-L. Defects in the Fas-mediated apoptotic pathway have been reported in colorectal cancer. In the present study, a variant of the Apc.sup.Min/+ mouse, a model for the human condition, Familial Adenomatous Polyposis (FAP), was generated with an additional deficiency of Fas (Apc.sup.Min/+ /Fas.sup.lpr) by cross-breeding Apc.sup.Min/+ mice with Fas deficient (Fas.sup.lpr) mice. One of the main limitations of the Apc.sup.Min/+ mouse model is that it only develops benign polyps. However, Apc.sup.Min/+ /Fas.sup.lpr mice presented with a dramatic increase in tumor burden relative to Apc.sup.Min/+ mice and invasive lesions at advanced ages. Proliferation and apoptosis markers revealed an increase in cellular proliferation, but negligible changes in apoptosis, while p53 increased at early ages. Fas-L was lower in Apc.sup.Min/+ /Fas.sup.lpr mice relative to Apc.sup.Min/+ cohorts, which resulted in enhanced inflammation. This study demonstrated that imposition of a Fas deletion in an Apc.sup.Min/+ background results in a more aggressive phenotype of the Apc.sup.Min/+ mouse model, with more rapid development of invasive intestinal tumors and a decrease in Fas-L levels. |
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ISSN: | 1932-6203 1932-6203 |
DOI: | 10.1371/journal.pone.0009070 |